11.2020 | THE SCIENTIST 23sles weren’t more likely to be malnour-
ished than those who survived the disease.
After public health officials implemented
a vaccination program with a live, atten-
uated measles inoculation in the area,
mortality within one year among 6- to
35-month-old children declined sharply,
Aaby and his team found—an effect not
fully explained by the drop in measles
infections.^5 The study was not a controlled
trial, however, so it remains impossible to
say if the vaccine was responsible.
To examine this apparent link between
the measles vaccine and non-measles mor-
tality in other settings, Aaby and his col-
leagues later analyzed the results of 10
cohort and case-control studies on measles
vaccination performed in seven developing
countries. The drop in mortality rates after
vaccination ranged from 30 percent to 86
percent, outstripping the reductions that
could be explained by measles mortality
rates alone. “These observations suggest that
standard titre measles vaccine may confer
a beneficial effect which is unrelated to the
specific protection against measles disease,”
the authors wrote in their 1995 BMJ paper.
They detected no such effects with two
other, non-live vaccines, diphtheria-tetanus-
pertussis (DTP) and a polio immunization.^6
It was around that time that Christine
Stabell Benn, then a medical student at Aar-
hus University, joined Aaby’s team at the Ban-
dim Health Project. She never left, and the
pair has now studied the nonspecific effects of
vaccines together for more than two decades,
becoming perhaps the most visible advocates
of those effects’ significance. Through further
studies, largely in Guinea-Bissau, Benn and
Aaby concluded that vaccines made of live,
attenuated pathogens—including BCG, the
live polio vaccine, and measles and smallpox
immunizations—provoke beneficial nonspe-
cific responses, while vaccines that use bits
of killed virus do not. In fact, Benn suggests
that non-live viruses actually make some
kids temporarily more susceptible to illnesses
other than the one they’ve been vaccinated
against. (See sidebar on page 26.)
Critics have questioned the existence and
strength of nonspecific effects, both benefi-
cial and deleterious. “A lot of the evidence is
very weak,” says Paul Fine, an epidemiologist
at the London School of Hygiene & Tropical
Medicine who has written letters in the past
to journals challenging the interpretations of
study results that indicate such effects. One
problem with observational studies, he says,
is that “vaccines in routine practice are not
allocated randomly, and kids who receive vac-
cines, in any population in the world outside
a vaccine trial, are not like the kids who don’t
receive vaccines. That’s been a main issue”
that can confound results, he says.To sort through the evidence on non-
specific effects and what implications they
might have for vaccine schedules, the World
Health Organization (WHO) convened a
working group in 2013 that included Fine,
Benn, and other experts. (The WHO for-
mulates recommendations for low- and
middle-income regions, but each country
develops a vaccination schedule based on
its own disease threats and other circum-
stances.) As part of its research, the group
commissioned an independent systematic
review of studies on nonspecific effects of
BCG, DTP, and the measles vaccine. The
review identified five clinical trials of BCG,
including the study of low birthweight
infants in Guinea-Bissau that had caught
Tobi Kollmann’s attention a few years ear-
lier, that found a 30 percent average reduc-
tion in mortality with the BCG vaccine. The
review’s authors noted that “tuberculosis is
now an infrequent cause of death in infants
and young children, so if BCG has an effect
on all cause mortality it is unlikely to be
entirely due to fewer deaths from that dis-
ease.” Similarly, the review identified four
controlled trials of the measles vaccine
that found an average decline in mortal-
ity of 26 percent, with deaths from mea-
sles contributing negligibly to that finding,
suggesting that the vaccine also protectedfrom other causes of death. The reviewers
found no clinical trials of nonspecific effects
for DTP, and all of the observational studies
addressing the question were classified as
having a high or very high risk of bias and
generated widely varying results.^7
The working group concluded in 2014
that “the systematic review neither excludes
nor confirms the possibility of beneficial
or deleterious non-specific immunological
effects of vaccines on all cause-mortality,”and also noted a lack of data on what the
mechanisms for such effects might be in
humans.^8 The authors suggested that the
WHO develop standard protocols for study-
ing nonspecific effects in an ethical and rig-
orous w ay, but it’s unclear what the current
status of that effort is. A WHO official told
The Scientist in July that she would look into
the matter but never provided the informa-
tion despite several follow-up inquiries.Recent developments
New studies on nonspecific effects have been
published since the working group con-
cluded, but a full picture of the phenome-
non has not yet come into focus. In a 2017
study of low–birth weight infants in Guinea-
Bissau, Benn and her colleagues found a 43
percent reduction in the mortality rate from
infectious disease in the first 28 days of life
among babies who received BCG soon after
birth compared with those who got it at
around six weeks of age, on the typical local
schedule.^9 Meanwhile, a study comparing
the effects of live and non-live polio vaccine
on toddlers in Bangladesh found that chil-
dren who received the live vaccine experi-
enced fewer episodes of diarrhea over the
following year than did those who received
the killed version.^10 And this September,
infectious diseases specialist Mihai NeteaTrials are now underway testing the BCG vaccine to see
if it can provide partial, temporary protection against
COVID-19—marking the first time a vaccine has been
trialed against a specific patho gen other than the one it
was designed fo r.